COL1A1 – Ehlers-Danlos Syndrome

COL1A1 encodes the pro-α1 chain of type I collagen, a major structural component of connective tissue. Ehlers-Danlos syndrome (EDS) encompasses a group of heritable connective tissue disorders characterized by skin hyperextensibility, joint hypermobility, and vascular fragility (PMID:8217561). Pathogenic variants in COL1A1 underlie classic and arthrochalasia EDS subtypes as well as OI-EDS overlap syndromes associated with compromised type I collagen turnover.

Initial evidence arose from a heterozygous splice-donor variant disrupting intron 6, resulting in exon 6 skipping and defective α1(I) processing in a patient with EDS type VII (PMID:1867198). Subsequent case reports identified missense substitutions such as c.934C>T (p.Arg312Cys) in multiple families presenting with classical EDS and arterial complications (PMID:31531849).

A founder homozygous missense variant c.2050G>A (p.Glu684Lys) segregated in two Saudi families with autosomal recessive EDS, demonstrating a clear genotype–phenotype correlation and a founder effect (PMID:33693443).

A cohort of 21 individuals from 13 families with overlapping OI/EDS phenotypes revealed eight recurrent COL1A1 variants predominantly affecting glycine residues near the N-propeptide cleavage site, reinforcing molecular homogeneity across the spectrum (PMID:31794058).

Functional analyses demonstrate that glycine substitutions and splice defects in the N-terminal helical domain delay or prevent procollagen N-propeptide removal by ADAMTS-2, leading to incorporation of pN-collagen into fibrils with aberrant ultrastructure and reduced thermal stability (PMID:15728585).

Together, extensive genetic and biochemical data support a definitive gene–disease relationship. COL1A1 molecular testing has high diagnostic yield in EDS subtypes and guides management, particularly for vascular surveillance.

Key Take-home: COL1A1 variants cause autosomal dominant Ehlers-Danlos syndrome through dominant-negative interference with collagen processing, warranting inclusion in diagnostic gene panels.

References

• Seminars in dermatology • 1993 • The Ehlers-Danlos syndromes PMID:8217561
• American Journal of Human Genetics • 1991 • Characterization of a COL1A1 splicing defect in a case of Ehlers-Danlos syndrome type VII PMID:1867198
• Clinical Genetics • 2020 • Classical Ehlers-Danlos syndrome with a propensity to arterial events PMID:31531849
• Global Medical Genetics • 2020 • Further Evidence of a Recessive Variant in COL1A1 as an Underlying Cause of Ehlers-Danlos Syndrome PMID:33693443
• Clinical Genetics • 2020 • COL1-related overlap disorder: A novel connective tissue disorder PMID:31794058
• Journal of Biological Chemistry • 2005 • Mutations near amino end of alpha1(I) collagen cause combined osteogenesis imperfecta/Ehlers-Danlos syndrome PMID:15728585

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